Browsing by Subject "Nucleotide"

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    Self-assembling Phosphoramidate Pronucleotides: Enzymatic Regulation and Application Towards Therapeutic Delivery
    (2019-08) West, Harrison
    Prior characterizations of the nucleoside phosphoramidate moiety have centered upon the ability of amine containing side-chains to mask the negative charge inherent to monophosphorylated nucleosides for the purpose of enhancing their passive movement across biological membranes. When used for the intracellular delivery of therapeutic nucleoside monophosphate analogs, these molecules are referred to as phosphoramidate “ProTides” and represent an important class of antiviral and anticancer prodrugs. The primary aim of this thesis to build upon these works and present the nucleoside phosphoramidate moiety as a multifunctional regulator of molecular self-assembly. Appendage of nucleoside phosphoramidates to molecules such as self-assembling peptides was shown to modulate the self-assembling properties of the molecules through alteration of the non-covalent interactions between individual monomers and nanostructure assemblies. Additionally, the nucleoside phosphoramidate moiety was found to impart enzyme responsive qualities. Histidine triad nucleotide binding proteins (Hints), an enzyme class that possesses phosphoramidase activity, were found to regulate the assembly of nucleoside phosphoramidate bearing nanostructures by inducing ionic interaction mediated crosslinking after enzymatic hydrolysis. Chemical modification of self-assembling peptides with nucleoside phosphoramidates bearing non-natural and therapeutic nucleosides was also achieved to effect the first ever demonstrated self-assembling phosphoramidate ProTides as one-component nanomedicines. The developed formulations are currently under investigation for localized delivery of cancer chemotherapeutic prodrugs